This proposal is aimed toward investigating the role of ribosomal S5-ikinase 2 (RSK2) and the Src l^inase Fyn in solar ultraviolet (solar UV)-induced skin carcinogenesis and to establish the Importance of RSK2 and Fyn as targets for chemoprevention of skin cancer. The hypothesis to be tested in the proposed work Is that RSK2 and Fyn each play a functional roie in solar UV-induced skin carcinogenesis, and therefore RSK2 and Fyn are each a significant target forthe development of chemoprevention agents to inhibit solar UV-induced non-melanoma skin cancer. The focus of this application is to study the role of RSK2 and Fyn in skin cancer development and develop specific RSK2 and Fyn Inhibitors for chemoprevention of skin cancer. Specific Aim 1. To study the role of RSK2 and Fyn in solar UV-induced skin carcinogenesis by using rsk2 and fyn gene knockout mice. Specific Aim 2. To identify and develop RSK2 and Fyn small molecule inhibitors and to test the effect of these inhibitors on tumor promoter-induced cell transformation. Specific Aim 3. To study the chemopreventive effect of newly discovered RSK2 and Fyn inhibitors in a solar UV-induced skin carcinogenesis mouse model. Specific Aim 4. To cross-validate RSK2 and Fyn each as a molecular target for chemoprevention of UVinduced skin cancer between mouse and human skin using tissue microarrays and reverse phase protein microarrays. This highly interactive and clinically translational research program project Focuses on the successful preclinical testing of targeted chemoprevention agents in innovative mouse models (Project 1 &2) followed by the design and implementation of clinical trails in at risk human populations (Project 3). Detailed descriptions of the decision-tree selection process as well as the interactions between Projects and Cores are found on the Resources Format Page.